1. Field of the Invention
The present invention relates to methods for inducing humoral and cellular immune responses against tumor cells and infectious agents. In particular, this invention is directed to methods for stimulating an immune response using an antibody that binds with an epitope of an antigen that is associated with a tumor or an infectious agent, and that contains at least one xcex1-galactosyl epitope. The present invention also is directed to mutated antibodies that contain at least one xcex1-galactosyl epitope in an engineered glycosylation site located in the constant region of the heavy chain.
2. Related Art
Transplants performed between phylogenetically disparate species are known to be susceptible to hyperacute rejection which is initiated by binding of xenoreactive natural antibodies to endothelium in the donor organ. Binding of these antibodies activates complement, leading to tissue injury and destruction of the graft. For example, porcine organs transplanted into primates are nearly always rejected within hours. Fukushima et al., Transplantation 57:923 (1994); Pruitt et al., Transplantation 57:363 (1994).
The major xenoantigen responsible for such rejection has recently been identified as a single carbohydrate structure, the xcex1-galactosyl epitope (Galxcex11-3Galxcex21-4GlcNAc-R). Galili et al., J. Exp. Med. 162:573 (1985); Galili et al., Proc. Nat""l Acad. Sci. USA 84:2369 (1987); Galili et al., J. Biol. Chem. 263:17755 (1988). The xcex1-galactosyl epitope is a glycosidic moiety that is expressed on the surface of cells from most mammalian species excluding humans and other old World primates (catarrhine primates). Expression of the xcex1-galactosyl epitope is mediated by the xcex11,3galactosyl transferase, an enzyme which is absent in old World primates and humans. In humans, as much as 1% of the total serum IgG is specific for the xcex1-galactosyl epitope. Galili et al., J. Exp. Med. 160:1519 (1984); Avila et al., J. Immunol. 142:2828 (1989). Significant levels of anti-xcex1-galactosyl (xe2x80x9canti-Galxe2x80x9d) IgM and IgA have also been reported.
Recently, LaTemple et al., Cancer Res. 56:3069 (1996), reported their studies on conferring xenograft characteristics to human cells by ex vivo treatment of tumor cells with neuraminidase and recombinant xcex11,3galactosyl transferase. The reaction converts the sialylated N-acetyllactosamine found on the human cell surface carbohydrate moieties into the xcex1-galactosyl epitope. Tumor cells armed with this epitope were reintroduced to the patients. The results indicated that anti-Gal antibodies help opsonize the tumor cells for phagocytosis by professional antigen presenting cells. LaTemple et al. hypothesized that the antigen presenting cells, after ingesting the xe2x80x9carmedxe2x80x9d tumor cells (tumor vaccines), would present the appropriate tumor-associated antigens (TAAs) to T cells, and that the patient would eventually develop a tumor-specific immunity. The exploitation of the hyperacute rejection mediated by anti-Gal activated complement, however, will require all tumor cells to be xe2x80x9cinducedxe2x80x9d with the xcex1-galactosyl epitope, and was not and could not be addressed by this approach. Moreover, the vaccines of LaTemple et al. require removal of a patient""s tumor cells, in vitro treatment with enzymes to produce the xcex1-galactosyl epitope, washing and lethal irradiation.
Galili et al., international publication No. WO 95/24924, describe a more general method for enhancing the immune response to an antigen by positioning an xcex1-galactosyl epitope either on or juxtaposed to the target antigen. According to this method, such a mixture stimulates opsonization by binding anti-Gal to xcex1-galactosyl epitopes which increases phagocytosis and subsequent processing of the target antigen by the macrophages. This general approach, however, also requires numerous ex vivo steps.
Therefore, the xcex1-galactosyl epitope has potential as a means to enhance the immune response to a target antigen, but a need exists for a method that does not depend upon extensive in vitro manipulation.
Accordingly, it is an object of the present invention to provide a method for enhancing the immune response to a tumor cell or infectious agent by using antibodies that contain the xcex1-galactosyl epitope to induce a patient""s immune system to target an antigen associated with the tumor cell or infectious agent.
Another object of this invention is to provide mutated antibodies that contain at least one engineered glycosylation site with a carbohydrate moiety comprising at least one xcex1-galactosyl epitope.
These and other objects are achieved, in accordance with one embodiment of the present invention by the provision of a method for stimulating humoral and cellular immune responses in a mammal against a tumor that expresses a tumor associated antigen (TAA) or against a disease caused by an infectious agent, comprising the step of:
(a) administering an xcex1-Gal antibody to the mammal, wherein the xcex1-Gal antibody comprises:
(i) an antibody component that binds with a specified target epitope, wherein the target epitope is an epitope of a TAA or an epitope of an antigen associated with an infectious agent, and
(ii) at least one xcex1-galactosyl epitope,
wherein the xcex1-Gal antibody can form a complex with cells that express said target epitope and antibodies that bind the xcex1-galactosyl epitope.